Abstract Rosetta is a molecular modeling program for the prediction and design of macromolecular structures. The capabilities of the program have been highlighted in community-wide assessments, and macromolecules designed with Rosetta are regularly validated experimentally with high-resolution structures. Rosetta is currently being applied to a variety of problems including: scaffold design for vaccine development, design of new therapeutic antibody formats, engineering of protein switches for inducible control of signaling pathways, and structure determination of protein monomers and complexes with sparse experimental constraints. Over 200 programmers at 50 laboratories are actively developing new capabilities within Rosetta, and 20,000 users have obtained free licenses to perform simulations with Rosetta. Just in the last two years, Rosetta developers have committed over 1300 revisions to the master version of Rosetta from their individual development branches. Maintaining the integrity, accuracy and usability of such a dynamic program is a significant challenge. This proposal is a competing renewal and is in response to a program announcement (PAR-11-028) for the continued development, maintenance and testing of biomedical software. Activities from the previous funding periods have been instrumental in the productive growth of Rosetta, these include the development of an automated testing system that checks and benchmarks every revision to the code base, code refactoring to ensure the use of modern programming practices and enable new scientific features, deployment of web servers for standardized, publicly-accessible Rosetta simulations, and user support through an online forum and tutorials. With this proposal our goal is to further increase the usefulness of Rosetta to expert and non- expert users by pursuing four specific aims: (1) promote rapid development of new algorithms and modeling strategies by maintaining and expanding our testing platform as well as creating automated protocols for ensuring code quality, (2) create a new job control system and scripting tools for multi-stage protocols with adaptive sampling, (3) convert to C++11 as the default build system for Rosetta, and (4) and provide user support through updated documentation, tutorials and workshops.